Institut National de la Recherche Agronomique, UMR1331, Toxalim, Research Centre in Food Toxicology, F-31027 Toulouse, France.
Toxicol Sci. 2012 May;127(1):29-41. doi: 10.1093/toxsci/kfs094. Epub 2012 Mar 22.
In rats, the widely used insecticide fipronil increases the clearance of thyroxine (T(4)). This effect is associated with a high plasma concentration of fipronil sulfone, the fipronil main metabolite in several species including rats and humans. In sheep, following fipronil treatment, fipronil sulfone plasma concentration and thyroid disruption are much lower than in rats. We postulated that fipronil biotransformation into fipronil sulfone by hepatic cytochromes P450 (CYP) could act as a potential thyroid disruptor. The aim of this study was to determine if fipronil sulfone treatment could reproduce the fipronil treatment effects on T(4) clearance and CYP induction in rats. Fipronil and fipronil sulfone treatments (3.4 μmol/kg/day per os, 14 days) increased total and free T(4) clearances to the same extent in THX + T(3), euthyroid-like rats. Both treatments induced a 2.5-fold increase in Ugt1a1 and Sult1b1 messenger RNA (mRNA) expressions and a twofold increase in UGT1A activity suggesting that T(4) elimination was mediated, at least in part, by hepatic uridine 5'-diphospho-glucuronosyltransferases (UGT) and/or sulfotransferases (SULT) induction. Both treatments induced a 10-fold increase in Cyp3a1 and Cyp2b2 mRNA expressions concomitant with a threefold increase in CYP3A immunoreactivity and a 1.7-fold increase in antipyrine clearance, a biomarker of CYP3A activity. All these results showed that fipronil sulfone treatment could reproduce the fipronil treatment effects on T(4) clearance and hepatic enzyme induction in rats. The potential of fipronil sulfone to act as a thyroid disruptor is all the more critical because it persists much longer in the organism than fipronil itself.
在大鼠中，广泛使用的杀虫剂氟虫腈会增加甲状腺素（T(4)）的清除率。这种作用与氟虫腈砜的高血浆浓度有关，氟虫腈砜是几种物种（包括大鼠和人类）中氟虫腈的主要代谢物。在绵羊中，在使用氟虫腈后，氟虫腈砜的血浆浓度和甲状腺紊乱比在大鼠中低得多。我们推测，肝脏细胞色素 P450（CYP）将氟虫腈生物转化为氟虫腈砜可能是一种潜在的甲状腺破坏剂。本研究的目的是确定氟虫腈砜处理是否能重现氟虫腈处理对大鼠 T(4)清除率和 CYP 诱导的作用。氟虫腈和氟虫腈砜处理（3.4 μmol/kg/天，经口，14 天）以相同的程度增加了总游离 T(4)的清除率，在 THX + T(3)、类似甲状腺功能正常的大鼠中。两种处理均使 Ugt1a1 和 Sult1b1 信使 RNA（mRNA）的表达增加了 2.5 倍，UGT1A 活性增加了两倍，表明 T(4)的消除至少部分是由肝尿苷 5'-二磷酸葡糖醛酸基转移酶（UGT）和/或磺基转移酶（SULT）诱导介导的。两种处理均使 Cyp3a1 和 Cyp2b2 mRNA 的表达增加了 10 倍，同时使 CYP3A 免疫反应性增加了 3 倍，安替比林清除率增加了 1.7 倍，这是 CYP3A 活性的生物标志物。所有这些结果表明，氟虫腈砜处理能重现氟虫腈处理对大鼠 T(4)清除率和肝酶诱导的作用。氟虫腈砜作为一种甲状腺破坏剂的可能性更加关键，因为它在体内的半衰期比氟虫腈本身长得多。
